Probing the Antiplasmodial Properties of Plakortinic Acids C and D: An Uncommon Pair of Marine Peroxide-Polyketides Isolated from a Two-Sponge Association of Plakortis symbiotica and Xetospongia deweerdtae Collected near Puerto Rico.

Plakortinic acids C (1) and D (2), an unseparable pair of endoperoxide polyketides isolated and purified from the symbiotic association of Caribbean Sea sponges Plakortis symbiotica-Xestospongia deweerdtae, underwent in vitro evaluation for antiplasmodial activity against the malaria parasite Plasmodium berghei using a drug luminescence assay. Initial screening at 10 µM revealed 50% in vitro parasite growth inhibition. The title compounds displayed antiplasmodial activity with an EC50 of 5.3 µM toward P. berghei parasites. The lytic activity against erythrocytes was assessed through an erythrocyte cell lysis assay, which showed non-lytic activity at lower concentrations ranging from 1.95 to 3.91 µM. The antiplasmodial activity and the absence of hemolytic activity support the potential of plakortinic acids C (1) and D (2) as promising lead compounds. Moreover, drug-likeness (ADMET) properties assessed through the pkCSM server predicted high intestinal absorption, hepatic metabolism, and volume of distribution, indicating favorable pharmacokinetic profiles for oral administration. These findings suggest the potential suitability of these metabolites for further investigations of antiplasmodial activity in multiple parasitic stages in the mosquito and Plasmodium falciparum. Notably, this study represents the first report of a marine natural product exhibiting the unique 7,8-dioxatricyclo[4.2.2.02,5]dec-9-ene motif being evaluated against malaria.

Actividad antiplasmodial de plantas usadas en la medicina tradicional contra la malaria en Cuba / Antiplasmodial activity of plant species used in traditional medicine for the control of malaria in Cuba

Introducción: Las plantas utilizadas en la medicina tradicional se exploran internacionalmente como fuentes valiosas de nuevos agentes antipalúdicos. Objetivos: Evaluar la actividad inhibidora in vitro frente a Plasmodium berghei de extractos de 27 especies de plantas utilizadas en el siglo pasado contra la malaria en Cuba, valorando los precedentes de estudios científicos de estas especies. Métodos: Se prepararon extractos etanólicos de 27 especies de plantas que se evaluaron in vitro a través de la inhibición de la esquizogonia de P. berghei ANKA. Se realizó una revisión basada en la consulta de artículos científicos para la clasificación de actividad basada en rangos de CI50. Resultados: Dieciséis especies mostraron precedentes de actividad inhibidora in vitro o su utilización en la medicina tradicional de otros países; siete especies no mostraron actividad coincidente. Solamente los extractos hidroalcohólicos de Euphorbia tithymaloides L. (partes aéreas) y Swietenia mahagoni (L.) Jacq. (corteza) fueron activos con CI50 ≤ 5 µg/mL, mientras para Colubrina arborescens (Mill.) Sarg. (corteza), la CI50 fue 14,3 ± 1,9 µg/mL. Extractos de 11 especies se probaron por el interés de su utilización en Cuba, sin precedentes etnobotánicos y experimentales disponibles. Entre estos, las partes aéreas de Baccharis halimifolia L. var. angustior DC; y de Oxandra lanceolata (Sw.) Baill. constituyeron fuentes antiplasmodiales de valores moderados de CI50. El resto de los extractos no fueron activos. Conclusiones: Estos resultados apoyan el uso en medicina tradicional en Cuba contra malaria de E. tithymaloides, S. mahagoni, C. arborescens, B. halimifolia y O. lanceolata, lo cual estimula a ampliar su estudio.

Introduction: Plants used in traditional medicine are studied worldwide as valuable sources of new antiplasmodial agents. Objective: To evaluate the in vitro inhibitory activity against Plasmodium berghei of extracts from 27 plant species used in the last century against malaria in Cuba and assess the previous scientific studies on these species. Methods: Ethanolic extracts from 27 plant species were prepared and evaluated in vitro by inhibiting the schizogony of P. berghei ANKA. A review of scientific papers was conducted to classify the activity based on IC50. Results: Sixteen species showed precedents of inhibitory activity in vitro or of their use in traditional medicine in other countries; seven species did not show coincident activity. Only hydroalcoholic extracts from Euphorbia tithymaloides L. (aerial parts) and Swietenia mahagoni (L.) Jacq. (bark) displayed activity at IC50 ≤ 5 µg/mL, while for Colubrina arborescens (Mill.) Sarg. (bark) IC50 was 14.3 ± 1.9 µg/mL. Extracts from 11 species, with no ethnobotanical and experimental precedents available, were evaluated given the interest of their use in Cuba. Of these species, the aerial parts of Baccharis halimifolia L. var. angustior DC and Oxandra lanceolata (Sw.) Baill. constituted antiplasmodial sources of moderate IC50 values. The rest of the extracts were not active. Conclusions: These results support the use of E. tithymaloides, S. mahagoni, C. arborescens, B. halimifolia y O. lanceolata in traditional medicine against malaria in Cuba, which stimulate further studies.

Black tea kombucha: Physicochemical, microbiological and comprehensive phenolic profile changes during fermentation, and antimalarial activity.

This study shows the changes in physicochemical and microbiological composition, and in the phenolic profile of black tea kombucha during fermentation. In addition, the antimalarial potential of the kombucha was evaluated. Ultra-performance liquid chromatography-mass spectrometry multiplex analysis (UPLC-MSE) results revealed a 1.7 log2 fold-change increase in phenolics with the fermentation time, with emphasis on the increase of phenolic acids (0.3 log2 fold-change). Over time there was degradation of flavonoids such as nepetin, hesperidin and catechin 5-O-gallate, to the detriment of the increase in phenolic acids such as gallic acid and cinnamic acid. In addition, black tea kombucha presented antiplasmodic activity against the 3D7 (sensitive chloroquine) and W2 (resistant to chloroquine) strains. Therefore, important changes in the black tea kombucha phenolic profile take place during fermentation, which may help in the development of kombuchas with higher bioactive potential and contribute to a better understanding of the kombucha fermentation process.

In vitro antiplasmodial activity of selected plants from the Colombian North Coast with low cytotoxicity.

Background: Plants are an important option in the treatment of malaria, especially in endemic regions, and are a less expensive and more accessible alternative with a lower risk of toxicity. Colombia has a great diversity of plants, and evaluation of natural extracts could result in the discovery of new compounds for the development of antimalarial drugs. The purpose of this work was to evaluate the in vitro antiplasmodial activity and the cytotoxicity of plant extracts from the Colombian North Coast against Plasmodium falciparum. Materials and Methods: The antiplasmodial activity of 12 plant species from the Colombian North Coast that are used in traditional medicine was evaluated through in vitro cultures of P. falciparum, and the cytotoxicity of extracts of these species to human cells was determined. Plant extracts with high antiplasmodial activity were subjected to preliminary phytochemical screening. Results: Extracts from five plants had promising antiplasmodial activity. Specifically, Bursera simaruba (Burseraceae) (bark), Guazuma ulmifolia Lam. (Malvaceae) (whole plant), Murraya exotica L. (Rutaceae) (leaves), Hippomane mancinella L. (Euphorbiaceae) (seeds), and Capparis odoratissima Jacq. (Capparaceae) (leaves). Extracts presented 50% inhibitory concentration values between 1 and 9 µg/ml. Compared to no extract, these active plant extracts did not show cytotoxic effects on mononuclear cells or hemolytic activity in healthy human erythrocytes. Conclusions: The results obtained from this in vitro study of antiplasmodial activity suggest that active plant extracts from the Colombian North Coast are promising for future bioassay-guided fractionation to allow the isolation of active compounds and to elucidate their mechanism of action against Plasmodium spp.

Eugenol carbonate activity against Plasmodium falciparum, Leishmania braziliensis, and Trypanosoma cruzi.

Neglected tropical diseases are a major health problem throughout the world, and there are few effective and safe drugs. In this study, we report the design and synthesis of a novel series of carbonates of eugenol using different aliphatic alcohols and N,N-carbonyldiimidazole. Spectroscopic techniques, including 1 H nuclear magnetic resonance (NMR), 13 C NMR, Fourier transform infrared, and high-resolution mass spectrometry, were used to confirm the structures of the synthesized compounds. In vitro and in silico studies of prodrugs of eugenol were performed to determine their antiplasmodial, trypanocidal, and leishmanicidal activities, and also their cytotoxicity. Compounds were highly active against Leishmania braziliensis and Plasmodium falciparum, whereas the activity shown for Trypanosoma cruzi was moderate. Molecular docking was used to determine a possible mode of action of eugenol against the dihydroorotate dehydrogenase of the three parasites (TcDHODH, LbDHODH, and PfDHODH). Notably, the docking results showed that eugenol not only has binding energy similar to that of the natural substrate (-7.2 and -7.1, respectively) but also has interactions with relevant biological residues of PfDHODH. This result indicates that eugenol could act as a substrate for PfDHODH in the pyrimidine biosynthesis pathway of P. falciparum. In conclusion, the combination of certain aliphatic alcohols and eugenol through a carbonate bond could significantly increase the antiparasitic activity of this class of compounds, which merits further studies.

Potent and selective antiplasmodial activity of marine sponges from Bahia state, Brazil.

This study evaluated the in vitro antiplasmodial and cytotoxic effects of 26 extracts from nine marine sponges collected in Salvador, Bahia state, Brazil. All assayed extracts were found to be potently active against Plasmodium falciparum W2 strain, with IC50 values ranging from 0.28 to 22.34 µg mL-1, and weakly cytotoxic against the human cell line WI-26-VA4 with CC50 values > 89 µg mL-1, thus displaying selectivity indices (SI) equal or higher than 17. Interestingly, some SI values exceeded 1,000. The highly potent and selective antiplasmodial activity of the assessed marine sponges is reported for the first time in this study.

Chemical Strategies towards the Synthesis of Betulinic Acid and Its More Potent Antiprotozoal Analogues.

Betulinic acid (BA, 3ß-hydroxy-lup-20(29)-en-28-oic acid) is a pentacyclic triterpene acid present predominantly in Betula ssp. (Betulaceae) and is also widely spread in many species belonging to different plant families. BA presents a wide spectrum of remarkable pharmacological properties, such as cytotoxic, anti-HIV, anti-inflammatory, antidiabetic and antimicrobial activities, including antiprotozoal effects. The present review first describes the sources of BA and discusses the chemical strategies to produce this molecule starting from betulin, its natural precursor. Next, the antiprotozoal properties of BA are briefly discussed and the chemical strategies for the synthesis of analogues displaying antiplasmodial, antileishmanial and antitrypanosomal activities are systematically presented. The antiplasmodial activity described for BA was moderate, nevertheless, some C-3 position acylated analogues showed an improvement of this activity and the hybrid models-with artesunic acid-showed the most interesting properties. Some analogues also presented more intense antileishmanial activities compared with BA, and, in addition to these, heterocycles fused to C-2/C-3 positions and amide derivatives were the most promising analogues. Regarding the antitrypanosomal activity, some interesting antitrypanosomal derivatives were prepared by amide formation at the C-28 carboxylic group of the lupane skeleton. Considering that BA can be produced either by isolation of different plant extracts or by chemical transformation of betulin, easily obtained from Betula ssp., it could be said that BA is a molecule of great interest as a starting material for the synthesis of novel antiprotozoal agents.

Synthesis of Novel 1,2,3-Triazole Derivatives of Isocoumarins and 3,4-Dihydroisocoumarin with Potential Antiplasmodial Activity In Vitro.

BACKGROUND: Malaria greatly affects the world health, having caused more than 228 million cases only in 2018. The emergence of drug resistance is one of the main problems in its treatment, demonstrating the need for the development of new antimalarial drugs. OBJECTIVE: Synthesis and in vitro antiplasmodial evaluation of triazole compounds derived from isocoumarins and a 3,4-dihydroisocoumarin. METHODS: The compounds were synthesized in 4 to 6-step reactions with the formation of the triazole ring via the Copper(I)-catalyzed 1,3-dipolar cycloaddition between isocoumarin or 3,4- dihydroisocoumarin azides and terminal alkynes. This key reaction provided compounds with an unprecedented connection of isocoumarin or 3,4-dihydroisocoumarin and the 1,2,3-triazole ring. The products were tested for their antiplasmodial activity against a Plasmodium falciparum chloroquine resistant and sensitive strains (W2 and 3D7, respectively). RESULTS: Thirty-one substances were efficiently obtained by the proposed routes with an overall yield of 25-53%. The active substances in the antiplasmodial test displayed IC50 values ranging from 0.68-2.89 µM and 0.85-2.07 µM against W2 and 3D7 strains, respectively. CONCLUSION: This study demonstrated the great potential of isocoumarin or 3,4-dihydroisocoumarin derivatives because practically all the tested substances were active against Plasmodium falciparum.

Alkyl and Aryl Derivatives Based on p-Coumaric Acid Modification and Inhibitory Action against Leishmania braziliensis and Plasmodium falciparum.

In low-income populations, neglected diseases are the principal cause of mortality. Of these, leishmaniasis and malaria, being parasitic, protozoan infections, affect millions of people worldwide and are creating a public health problem. The present work evaluates the leishmanicidal and antiplasmodial action of a series of twelve p-coumaric acid derivatives. Of the tested derivatives, eight presented antiparasitic activities 1-3, 8-12. The hexyl p-coumarate derivative (9) (4.14 ± 0.55 µg/mL; selectivity index (SI) = 2.72) showed the highest leishmanicidal potency against the Leishmania braziliensis amastigote form. The results of the molecular docking study suggest that this compound inhibits aldehyde dehydrogenase (ALDH), mitogen-activated kinase protein (MPK4), and DNA topoisomerase 2 (TOP2), all of which are key enzymes in the development of Leishmania braziliensis. The data indicate that these enzymes interact via Van der Waals bonds, hydrophobic interactions, and hydrogen bonds with phenolic and aliphatic parts of this same compound. Of the other compounds analyzed, methyl p-coumarate (64.59 ± 2.89 µg/mL; IS = 0.1) demonstrated bioactivity against Plasmodium falciparum. The study reveals that esters presenting a p-coumarate substructure are promising for use in synthesis of derivatives with good antiparasitic profiles.

Improvement of antimalarial activity of a 3-alkylpiridine alkaloid analog by replacing the pyridine ring to a thiazole-containing heterocycle: Mode of action, mutagenicity profile, and Caco-2 cell-based permeability.

The development of new antimalarial drugs is urgent to overcome the spread of resistance to the current treatment. Herein we synthesized the compound 3, a hit-to­lead optimization of a thiazole based on the most promising 3-alkylpyridine marine alkaloid analog. Compound 3 was tested against Plasmodium falciparum and has shown to be more potent than its precursor (IC50 values of 1.55 and 14.7 µM, respectively), with higher selectivity index (74.7) for noncancerous human cell line. This compound was not mutagenic and showed genotoxicity only at concentrations four-fold higher than its IC50. Compound 3 was tested in vivo against Plasmodium berghei NK65 strain and inhibited the development of parasite at 50 mg/kg. In silico and UV-vis approaches determined that compound 3 acts impairing hemozoin crystallization and confocal microscopy experiments corroborate these findings as the compound was capable of diminishing food vacuole acidity. The assay of uptake using human intestinal Caco-2 cell line showed that compound 3 is absorbed similarly to chloroquine, a standard antimalarial agent. Therefore, we present here compound 3 as a potent new lead antimalarial compound.

A Comprehensive View on (-)-7-Oxo-ent-kaur-16-en-19-oic Acid, the Major Constituent of Xylopia sericea Leaves Extract: Complete NMR Assignments, X-Ray Crystallographic Structure, in Vitro Antimalarial Activity and Cytotoxicity.

Bioguided fractionation of Xylopia sericea antiplasmodial dichloromethane leaves extract led to the isolation of (-)-7-oxo-ent-kaur-16-en-19-oic acid (C20 H28 O3 ) that was identified by a combination of 1D and 2D NMR experiments (COSY, HMBC, HSQC, HSQC-TOCSY, HSQC-NOESY and NOESY) and by X-ray crystallography. A feature to be pointed out is its (4R) configuration that was inferred from the NOE experiments (HSQC-NOESY and NOESY) and X-ray crystallography. In vitro evaluation of this rare diterpene acid against the chloroquine-resistant strain Plasmodium falciparum W2 by the PfLDH method showed it disclosed a low antiplasmodial activity and was not cytotoxic to HepG2 cells (CC50 862.6±6.7 µm) by the MTT assay. The unequivocal NMR signals assignments, the X-ray crystallographic structure, the assessment to the bioactivities and the occurrence this diterpene in X. sericea are reported here for the first time.

Antiplasmodial activity and cytotoxicity, isolation of active alkaloids, and dereplication of Xylopia sericea leaves ethanol extract by UPLC-DAD-ESI-MS/MS.

OBJECTIVES: To assess the antiplasmodial activity of the ethanol extract of Xylopia sericea leaves, Annonaceae, often associated with antimalarial use and to perform a bioguided isolation of active compounds. METHODS: Dereplication of ethanol extract by the UPLC-DAD-ESI-MS/MS technique allowed the identification of the major constituents, isolation and identification of alkaloids. The antiplasmodial and cytotoxic activity of the extract, fractions and isolated compounds was evaluated against the chloroquine-resistant W2 strain Plasmodium falciparum and HepG2 cells, respectively. KEY FINDINGS: Ethanol extract showed high reduction of parasitemia as well as moderate cytotoxicity (86.5 ± 3.0% growth inhibition at 50 µg/ml and CC50 72.1 ± 5.1 µg/ml, respectively). A total of eight flavonoids were identified, and two aporphine alkaloids, anonaine and O-methylmoschatoline, were isolated. Anonaine disclosed significant antiplasmodial effect and moderate cytotoxicity (IC50 23.2 ± 2.7 µg/ml, CC50 38.3 ± 2.3 µg/ml, SI 1.6) while O-methylmoschatoline was not active against P. falciparum and showed a low cytotoxicity (33.5 ± 1.9% growth inhibition at 50 µg/ml, CC50 274.4 ± 0.5 µg/ml). CONCLUSIONS: Characterization of Xylopia sericea leaves ethanol extract by UPLC-DAD-ESI-MS/MS as well as its antiplasmodial activity and the occurrence of anonaine and O-methylmoschatoline in this Xylopia species are reported by the first time.

Secochiliolide ester derivatives: Preparation and evaluation of their antitrypanosomal and antimalarial efficacy.

In the present study, a series of new esters of secochiliolide acid (SA), a diterpene isolated from Nardophyllum bryoides, were synthesized in good yield. All compounds were evaluated for their in vitro antiparasitic properties (on Plasmodium falciparum and Trypanosoma brucei brucei) and cytotoxicity (on WI38, normal mammalian cells). They displayed moderate antitrypanosomal activity with IC50 values between 2.55 and 18.14 µm, with selectivity indices >10, and low antiplasmodial effects with IC50  > 29 µm. The only exception was the n-hexyl ester of SA, which showed a strong and selective antiplasmodial activity (IC50  = 1.99 µm and selectivity index = 117.0). The in vivo antimalarial efficacy of this compound was then assessed according to the 4-day suppressive test of Peters in mice. An intraperitoneal treatment at 50 mg kg-1  day-1 induced a slight parasitaemia reduction by 56% which was statistically significant on day 4 post-infection and an increase in the survival time.

Aspidosperma species: A review of their chemistry and biological activities.

ETHNOPHARMACOLOGICAL RELEVANCE: Species of Aspidosperma are known popularly as "peroba, guatambu, carapanaúba, pau-pereiro" and "quina". The genus can be found in the Americas, mainly between Mexico and Argentina. Many species of Aspidosperma are used by the population in treating cardiovascular diseases, malaria, fever, diabetes and rheumatism. The phytochemical aspects of the species of the genus Aspidosperma have been studied extensively. The monoterpene indole alkaloids are the main secondary metabolites in Aspidosperma species, and about 250 of them have been isolated showing a considerable structural diversity. Several of them have showed some important pharmacological activities. Aspidosperma subincanum Mart. and Aspidosperma tomentosum Mart. (Apocynaceae) are Brazilian species widely used by the population to treat diabetes mellitus, hypercholesterolemia. The pharmacological activities of both species have been investigated and the biological properties described can be related to their isolated indole alkaloids. However, more pharmacological studies are needed in order to justify the use of these species in folk medicine. In this review, we present reports mainly focused on chemical and biological studies and their relationship with the ethnopharmacological use of both Aspidosperma species. AIM OF THE STUDY: The aim of this review is to present their ethnopharmacological use as correlated to their biological activities as described for the extracts and isolated compounds from Aspidosperma subincanum Mart. and Aspidosperma tomentosum Mart. In addition, some aspects related to the biosynthetic pathways are discussed, also NMR assignments and some synthesis information about indole alkaloids from both Aspidosperma species are included. MATERIAL AND METHODS: The bibliographic search was made in theses and dissertations using some databases such as NDLTD (Networked Digital Library of Theses and Dissertations), OATD (Open Access Theses and Dissertations) and Google Scholar. More data were gathered from books, Brazilian journals and articles available on electronic databases such as, Google Scholar, PubChem, Scifinder, Web of Science, SciELO, PubMed and Science Direct. Additionally, the Google Patents and Espacenet Patent Search (EPO) were also consulted. The keywords Aspidosperma, A. subincanum, A. tomentosum, indole alkaloids were used in the research. The languages were restricted to Portuguese, English and Spanish and references were selected according to their relevance. RESULTS: A. subincanum Mart. and A. tomentosum Mart. (Apocynaceae) are Brazilian species widely used by the population to treat a few diseases. Extracts and isolated compounds of both species have shown antitumor and antimalarial activities. The antitumor activity of isolated compounds has been extensively studied. However, the antiplasmodial activity needs to be investigated further as well as the anti-inflammatory, anti-hyperlipidemic and anorexigenic activities. From A. subincanum twenty-one indole alkaloids were isolated and some of them have been extensively studied. From the leaves and bark of A. tomentosum four alkaloids and one flavonoid were isolated. Furthermore, CG-MS analysis of seeds, branches, leaves and arils identified nine indole alkaloids. Stemmadenine has been proposed as a precursor of indole alkaloids obtained from some species of Aspidosperma. Many of the biosynthetic steps have been characterized at the enzymatic level and appropriate genes have been identified, however, other steps have yet to be investigated and they are still controversial. Some isolated alkaloids from A. subincanum and A. tomentosum were identified only by mass spectrometry. In many cases, their NMR data was either not available or was incomplete. The described meta-analysis of the available NMR data revealed that the chemical shifts belonging to the indole ring might be used to characterize this class of alkaloids within complex matrices such as plant extracts. The biological activities and the structural complexity of these compounds have stimulated the interest of many groups into their synthesis. In this review, some information about the synthesis of indole alkaloids and their derivatives was presented. CONCLUSIONS: A. subincanum and A. tomentosum are used by the population of Brazil to treat many diseases. A few biological activities described for the extracts and isolated compounds of both species are in agreement with the ethnopharmacological use for others species of Aspidosperma, such as, antimalarial, the treatment of diabetes and other illnesses. These species are sources of leading compounds which can be used for developing new drugs. In addition, other biological activities reported and suggested by ethnopharmacological data have yet to be investigated and could be an interesting area in the search for new bioactive compounds.

Huberine, a New Canthin-6-One Alkaloid from the Bark of Picrolemma huberi.

A new alkaloid, Canthin-6-one, Huberine (1), together with three known compounds including 1-Hydroxy-canthin-6-one (2), Canthin-6-one (3) and stigma sterol (4), were isolated from the stem bark of Picrolemma huberi. The isolation was achieved by chromatographic techniques and the purification was performed on a C18 column using acetonitrile/water (90:10, v/v) with 0.1% formic acid as the mobile phase. The structural elucidation was performed via spectroscopic methods, notably 1D- and 2D-NMR, UV, IR, MS and HRMS. The antiplasmodial activity of the compounds was studied.

Synthesis, antimalarial activity in vitro, and docking studies of novel neolignan derivatives.

The absence of effective vaccines against malaria and the difficulties associated with controlling mosquito vectors have left chemotherapy as the primary control measure against malaria. However, the emergence and spread of parasite resistance to conventional antimalarial drugs result in a worrisome scenario making the search for new drugs a priority. In the present study, the activities of nine neolignan derivatives were evaluated as follows: (i) against blood forms of chloroquine-resistant Plasmodium falciparum (clone W2), using the tritiated hypoxanthine incorporation and anti-HRPII assays; (ii) for cytotoxic activity against cultured human hepatoma cells (HepG2); and (iii) for intermolecular interaction with the P. falciparum cysteine protease of falcipain-2 (F2) by molecular docking. The neolignan derivatives 9 and 10 showed activity against the blood form of the chloroquine-resistant P. falciparum clone W2 and were not cytotoxic against cultured human hepatoma cells. A molecular docking study of these two neolignans with FP2 revealed several intermolecular interactions that should guide the design of future analogs.

Caffeoylquinic acids from antiplasmodial active extract of Xanthium cavanillesii fruits and their molecular modelling studies.

The antiplasmodial active extract of Xanthium cavanillesii contains 3,4-dicaffeoyl quinic acid (3,4-DCQA), 3,5-dicaffeoyl quinic acid (3,5-DCQA) and 1,3,5-tricaffeoyl quinic acid (1,3,5-TCQA). These results inspired us to investigate the interaction of these molecules with a promising validated target of Plasmodium, PfATP6 orthologue of mammalian Ca+2-ATPase. Models of this receptor were obtained through comparative modelling. Afterwards, molecular docking studies were used to identify possible interaction modes of these caffeoyl quinic derivatives on the binding site. The 1,3,5-TCQA had the best energy, but all of these had better energy than thapsigargin, a non-competitive inhibitor of the sarco/endoplasmatic reticulum Ca+2-ATPase (SERCA).

A New Alkamide with an Endoperoxide Structure from Acmella ciliata (Asteraceae) and Its in Vitro Antiplasmodial Activity.

From the aerial parts of Acmella ciliata (H.B.K.) Cassini (basionym Spilanthes ciliata Kunth; Asteraceae), three alkamides were isolated and identified by mass- and NMR spectroscopic methods as (2E,6E,8E)-N-isobutyl-2,6,8-decatrienamide (spilanthol, (1)), N-(2-phenethyl)-2E-en-6,8-nonadiynamide (2) and (2E,7Z)-6,9-endoperoxy-N-isobutyl-2,7-decadienamide (3). While 1 and 2 are known alkamides, compound 3 has not been described until now. It was found that the unusual cyclic peroxide 3 exists as a racemate of both enantiomers of each alkamide; the 6,9-cis- as well as the 6,9-trans-configured diastereomers, the former represents the major, the latter the minor constituent of the mixture. In vitro tests for activity against the human pathogenic parasites Trypanosoma brucei rhodesiense and Plasmodium falciparum revealed that 1 and 3 possess activity against the NF54 strain of the latter (IC50 values of 4.5 and 5.1 µM, respectively) while 2 was almost inactive. Compound 3 was also tested against multiresistant P. falciparum K1 and was found to be even more active against this parasite strain (IC50 = 2.1 µM) with considerable selectivity (IC50 against L6 rat skeletal myoblasts = 168 µM).

Actividad anti-plasmodial de especies de Solanaceae presentes en Cuba / Antiplasmodial activity of Solanaceae species present in Cuba

Introducción: el control de la malaria depende en gran medida de una terapia efectiva. Muchos de los anti-maláricos actuales son de origen natural. Especies de la flora cubana contienen metabolitos anti-Plasmodium. En este estudio, se identifican extractos de Solanaceae con actividad antiplasmodial promisoria. Objetivo: evaluar la actividad esquizonticida frente a Plasmodium berghei de 31 extractos de 7 especies, correspondientes a 5 géneros de plantas de Solanaceae, colectadas en el occidente de nuestro país y sin antecedentes de un estudio similar. Métodos: se prepararon 31 extractos hidroalcohólicos (90 y 30 por ciento etanol) de diferentes órganos de: Brunfelsia undulata Sw., Datura stramonium L. var. tatula (L.) Torr., Physalis solanaceus (Schltdl.) Axelius, Solandra longiflora Tuss., Solanum myriacanthum Dunal, Solanum seaforthianum And. ySolanum umbellatum Mill.La actividad de los extractos se evaluó in vitro frente a P. berghei y se determinó su citotoxicidad frente a fibroblastos humanos MRC-5. Resultados: los extractos deB. undulata y S. umbellatumfueron inactivos.El extracto de tallos de S. seaforthianummostró la actividad antiplasmodial más potente (CI50 = 3,9µg/mL) con excelentes electividad (18,2). Conclusiones: se demostró la actividad anti-plasmodial in vitro de extractos de cinco especies de Solanaceae sin antecedentes de esta acción farmacológica. Se identificó un extracto con potente actividad esquizonticida frente a P. berghei y con excelente selectividad. Este resultado nos anima a continuar el estudio de la preparación vegetal de S. seaforthianum(AU)

BbMP-1, a new metalloproteinase isolated from Bothrops brazili snake venom with in vitro antiplasmodial properties.

This study describes the biochemical and functional characterization of a new metalloproteinase named BbMP-1, isolated from Bothrops brazili venom. BbMP-1 was homogeneous on SDS-PAGE, presented molecular mass of 22,933Da and pI 6.4. The primary structure was partially elucidated with high identity with others metalloproteinases from Viperidae venoms. The enzymatic activity on azocasein was evaluated in different experimental conditions (pH, temperature). A significant reduction in enzyme activity after exposure to chelators of divalent cations (EDTA), reducing agents (DTT), pH less than 5.0 or temperatures higher than 45 °C was observed. BbMP-1 showed activity on fibrinogen degrading Aα chain quickly and to a lesser extent the Bß chain. Also demostrated to be weakly hemorrhagic, presenting however, significant myotoxic and edematogenic activity. The in vitro activity of BbMP-1 against Plasmodium falciparum showed an IC50 of 3.2 ± 2.0 µg/mL. This study may help to understand the pathophysiological effects induced by this group of toxin and their participation in the symptoms observed in cases of snake envenomation. Moreover, this result is representative for this group of proteins and shows the biotechnological potential of BbMP-1 by the demonstration of its antiplasmodial activity.